Structural Analysis of Siderophore Biosynthesis (2002-2003)

The long-term goal of this project is to understand in atomic detail the molecular mechanisms of siderophore production by Pseudomonas aeruginosa. The siderophores pyochelin and pyoverdin are virulence factors for P. aeruginosa. If siderophore production is disrupted, the bacteria cannot acquire the iron required for survival in iron limiting environments such as the human host. Pseudomonas aeruginosa are notoriously antibiotic resistant and are able to colonize immuno-compromised patients and the lungs of patients with cystic fibrosis. Other deadly bacteria use chemically similar siderophores in colonization of human tissues including plague bacteria (Yersinia pestis) and cholera bacteria (Vibrio cholerae). Therefore, structural information about the biosynthetic enzymes of pyochelin and pyoverdin may provide new anti-microbial targets not only for the rational drug design of antibiotics for CF therapy, and secondary infections due to immunodepression in cancer, AIDS and burn patients, but also for the fight against bioterrorism.

The specific aims are:

To structurally characterize the enzymes that produce pyochelin from salicylate and cysteine.

To solve the three-dimensional structures of the enzymes which convert chorismate to salicylate.